Collagen is the major protein component of the extracellular matrix of all connective tissue, including skin, tendons, bones, cartilage, blood vessels and ligaments. It is well established that collagen plays a critical role in establishing and maintaining the structure of human tissues. Recent studies have revealed that collagen interacts with cells in connective tissues and transduces essential signals for regulation of cell anchorage, migration, proliferation, differentiation and survival.
It is well known that ascorbic acid is required for the hydroxylation of collagen. Ascorbic acid is a co-factor of prolyl hydroxylase and lysyl hydroxylase. Hydroxylation of proline is essential for the stabilization of collagen triple helix, while hydroxylation of lysine is required for collagen crosslinking. Compromised collagen production associated with ascorbic acid deficiency is believed to result in impaired wound healing, and may have other adverse effects.
Shukla, and Mason et al. (Shukla, S. P., Plasma and Urinary Ascorbic Acid Levels in the Postoperative Period, Experientia 25: 704, 1969) suggested that surgical stress resulted in increased ascorbic acid requirements. However, Levenson et al. (Levenson et al., Vitamins in Acute Illness, Annals of Surgery 24 (5) p 840-856 1946) reported plasma ascorbic acid levels below normal values in severely injured patients. In some patients, plasma levels of ascorbic acid were immeasurable within a few hours following major injury. Levenson et al. also reported that blood levels of ascorbic acid remained subnormal even with daily 1000 mg intramuscular injections through the eighth day. The incorporation of ascorbic acid into implantable devices and tissue engineering scaffolds for a localized and controlled release formulations of ascorbic acid in the sites where collagen biosynthesis is required would be desirable for enhancing tissue repair and regeneration.
Controlled release formulations of ascorbic acid phosphate have been prepared by solvent casting. For example, Hyongbum Kim et al. (Kim H. et al (2003): Sustained Release of Ascorbic-2-phosphate and Deamethasone from Porous PLGA Scaffolds for Bone Tissue Engineering Using Mesenchymal Stem Cells, Biomaterials 24:4671-4679) described a porous PLGA scaffold for controlled release of ascorbic acid phosphate, a stable form of ascorbic acid. The porous PLGA matrices containing ascorbic acid phosphate and dexamethasone were prepared by solvent casting/particulate leaching methods. There are disadvantages of using known solvent casting methods in preparing ascorbic acid phosphate controlled release formulations. The disadvantages include the need to remove residual solvent, the difficulty in or impossibility of preparing three dimensional (3-D) medical device parts by solvent casting, and there is a substantial burst of ascorbic acid phosphate release from solvent cast structures both in vivo and in vitro. Therefore, there is a need in this art for novel and improved methods for making ascorbic acid controlled release compositions, and medical devices and components made from such compositions.